2q31 microdeletion syndrome with the velocardiofacial phenotype and review of the literature: a case report.

BACKGROUND: The 2q31 deletion results in a distinct phenotype characterized by varying degrees of developmental delay, short stature, facial dysmorphism, and variable limb defects. Dysmorphic features include microcephaly, downslanting palpebral fissures, a long and flat philtrum, micrognathia, and dysplastic, low-set ears. To date, comparative genomic hybridization has identified this deletion in 38 patients. Consequently, additional patients with comprehensive clinical data are required to fully understand the spectrum of clinical manifestation associated with a deletion in the 2q31 cytoband. CASE PRESENTATION: We present the case of an 8-year-old female patient with clinical features of velocardiofacial syndrome, which include facial dysmorphism, congenital heart disease (persistent truncus arteriosus and ostium secundum-type atrial septal defect), and a seizure syndrome. Array comparative genomic hybridization revealed a non-continous deletion spanning cytobands 2q31.1-to 2q31.3, confirming a diagnosis of 2q31 microdeletion syndrome. The patient has undergone supportive therapies for swallowing and speech. Additionally, we provide a review of the literature on previous cases to give context. CONCLUSION: In this report, we present the first documented case of a complex, discontinuous deletion spanning in the 2q31-2q32 regions. This case contributes to our understanding of the phenotypic and mutational spectrum observed in individuals with deletions in these cytobands. It underscores the significance of employing high-resolution techniques and comprenhensive analysis in diagnosing patients with complex phenotypes. Such approaches are crucial for differentiating this condition from more common microdeletion syndromes, such as the 22q11 deletion syndrome.

Novel risk loci for COVID-19 hospitalization among admixed American populations.

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

Mortality in Patients with 22q11.2 Rearrangements.

The 22q11.2 region is highly susceptible to genomic rearrangements leading to multiple genomic disorders, including 22q11.2 microdeletion syndrome (22q11.2 DS) (MIM# 188400), 22q11.2 microduplication syndrome (MIM# 608363), supernumerary der(22)t(11;22) syndrome (also known as Emanuel Syndrome; MIM# 609029), and Cat Eye Syndrome (MIM# 115470). In this study, we present data on causes of mortality, average age of death, and the existing associated risk factors in patients with 22q11.2 rearrangements. Our cohort included 223 patients (120 males and 103 females) with confirmed diagnoses of 22q11.2 rearrangements diagnosed through molecular techniques (FISH, MLPA, and CMA). Relatives from patients who have been molecularly confirmed with 22q11.2 rearrangements have also been added to the study, regardless of the presence or absence of symptoms. Of these 223 individuals, 21 (9.4%) died. Deceased patients' rearrangements include 19 microdeletions, 1 microduplication, and 1 patient with a marker chromosome. The median age of death was 3 months and 18 days (ranging from 3 days to 34 years). There were 17 patients who died at pediatric age (80.95%), 3 died at adult age (14.28%), and for 1 of whom, the age of death is unknown (4.76%). Eighteen patients were White Mediterranean (European non-Finnish) (85.71%) whereas three were Amerindian (South American) (14.28%). Mortality from cardiac causes accounted for 71.42%. The second most frequent cause of death was sepsis in two patients (9.52%). One patient died from respiratory failure (4.76%) and one from renal failure (4.76%). Information regarding the cause of death was not available in two patients (9.52%). Most patients who died were diagnosed within the first week of life, the majority on the first day. This study adds additional information on mortality in one of the largest cohorts of patients with 22q11.2 rearrangements in more than 30 years of follow-up.

Identification of copy-number variants in patients with overgrowth disorders.

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that the weight, height or the head circumference are above the 97th centile or 2-3 standard deviations above the mean for age, gender, and ethnic group. Several copy-number variants (CNVs) have been associated with the development of OGS, such as the 5q35 microdeletion or the duplication of the 15q26.1-qter, among many others. In this study, we have applied 850K SNP-arrays to 112 patients and relatives with OGS from the Spanish OverGrowth Registry Initiative. We have identified CNVs associated with the disorder in nine individuals (8%). Subsequently, whole genome sequencing (WGS) analysis was performed in these nine samples in order to better understand these genomic imbalances. All the CNVs were detected by both techniques, settling that WGS is a useful tool for CNV detection. We have found six patients with genomic abnormalities associated with previously well-established disorders and three patients with CNVs of unknown significance, which may be related to OGS, based on scientific literature. In this report, we describe these findings and comment on genes associated with OGS that are located within the CNV regions.

Phenotypic spectrum and tumor risk in Simpson-Golabi-Behmel syndrome: Case series and comprehensive literature review.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum.

Non-immune hydrops fetalis is associated with bi-allelic pathogenic variants in the MYB Binding Protein 1a (MYBBP1A) gene.

Non-immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF.

Is Nuchal Translucency of 3.0-3.4 mm an Indication for cfDNA Testing or Microarray? - A Multicenter Retrospective Clinical Cohort Study.

INTRODUCTION: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the nuchal translucency (NT) range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. METHODS: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased first trimester combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. RESULTS: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases, trisomy 21, 18, or 13 were found. In 0.7% (2/271) of cases, sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV >10 Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). CONCLUSION: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0-3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered, and counseling on NIPT should include the test limitations that may result in NIPT false-negative results in a substantial percentage of fetuses.

Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder.

DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.

NGS Custom Panel Implementation in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital.

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by deficiencies in communication, social interaction, and repetitive and restrictive behaviors. The discovery of genetic involvement in the etiology of ASD has made this condition a strong candidate for genome-based diagnostic tests. Next-generation sequencing (NGS) is useful for the detection of variants in the sequence of different genes in ASD patients. Herein, we present the implementation of a personalized NGS panel for autism (AutismSeq) for patients with essential ASD over a prospective period of four years in the clinical routine of a tertiary hospital. The cohort is composed of 48 individuals, older than 3 years, who met the DSM-5 (The Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for ASD. The NGS customized panel (AutismSeq) turned out to be a tool with good diagnostic efficacy in routine clinical care, where we detected 12 "pathogenic" (including pathogenic, likely pathogenic, and VUS (variant of uncertain significance) possibly pathogenic variations) in 11 individuals, and 11 VUS in 10 individuals, which had previously been negative for chromosomal microarray analysis and other previous genetic studies, such as karyotype, fragile-X, or MLPA/FISH (Multiplex Ligation dependent Probe Amplification/Fluorescence in situ hybridization) analysis. Our results demonstrate the high genetic and clinical heterogeneity of individuals with ASD and the current difficulty of molecular diagnosis. Our study also shows that an NGS-customized panel might be useful for diagnosing patients with essential/primary autism and that it is cost-effective for most genetic laboratories.

A Spanish Family with Gordon Syndrome Due to a Variant in the Acidic Motif of WNK1.

(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS.

Snijders Blok-Campeau Syndrome: Description of 20 Additional Individuals with Variants in CHD3 and Literature Review.

Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51-74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.

Lamb-Shaffer syndrome: 20 Spanish patients and literature review expands the view of neurodevelopmental disorders caused by SOX5 haploinsufficiency.

Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.

Cognitive-Behavioral Profile in Pediatric Patients with Syndrome 5p-; Genotype-Phenotype Correlationships.

(1) Background: 5p minus Syndrome (S5p-) is a neurodevelopmental disorder caused by a deletion in the short arm of chromosome 5. Among the phenotypic characteristics of S5p-, the most characteristic and representative element is a monochromatic cry with a high-pitched tone reminiscent of a cat's meow. Individuals may also show great phenotypic heterogeneity and great genetic variability. Regarding cognitive-behavioral aspects of the syndrome, the studies are scarce and do not establish a general profile of the main cognitive-behavioral particularities that this syndrome presents. The main objective of this work was to describe the development profile of a cohort of 45 children with 5p minus Syndrome, concerning the biomedical, genetic, cognitive, and behavioral aspects. Establishing putative genotype-phenotype (cognitive-behavioral profiles) relationships in our cohort, from an interdisciplinary approach. (2) Methods: A selection of instruments of measures was selected for neuropsychological assessment (3) Results: In general, children with S5p- have a higher cognitive level than a communicative and motor level. Language difficulties, especially expressive ones, influence the frequency and severity of the most frequent behavioral problems in S5p. The most significant problem behavior of children with S5p-, especially girls, is self-harm. Compulsive behavior, limited preferences, and interest in monotony are significantly more frequent in subjects with better cognitive levels. We also find a significant correlation between the size of the loss of genetic material on 5p and the cognitive level of the subjects. (4) Conclusions: We described for the first time, the cognitive-behavioral profile of a cohort of minors with S5p-. Remarkably, it was found that language, especially of an expressive nature, modulates the most frequent behavioral aspects in subjects with lower cognitive levels, so it is essential to develop verbal or alternative communication strategies adjusted to these individuals.

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature.

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

Adult experiences in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context.

Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital.

Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with it. The use of chromosomal microarray analysis (CMA) has proven to be a rapid and effective method for detecting both small and large deletions and duplications associated with ASD. In this article, we present the implementation of CMA as a first-tier test in our clinical laboratory for patients with primary ASD over a prospective period of four years. The cohort was composed of 212 individuals over 3 years of age, who met DSM-5 diagnostic criteria for ASD. The use of a customized array-CGH (comparative genomic hybridization) design (KaryoArray®) found 99 individuals (45.20%) with copy number variants (CNVs); 34 of them carried deletions (34.34%) and 65 duplications (65.65%). A total of 28 of 212 patients had pathogenic or likely pathogenic CNVs, representing approximately 13% of the cohort. In turn, 28 out of 212 (approximately 12%) had variants of uncertain clinical significance (VUS). Our findings involve clinically significant CNVs, known to cause ASD (syndromic and non-syndromic), and other CNVs previously related to other comorbidities such as epilepsy or intellectual disability (ID). Lastly, we observed new rearrangements that will enhance the information available and the collection of genes associated with this disorder. Our data also highlight that CMA could be very useful in diagnosing patients with essential/primary autism, and demonstrate the existence of substantial genetic and clinical heterogeneity in non-syndromic ASD individuals, underscoring the continued challenge for genetic laboratories in terms of its molecular diagnosis.

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

Consensus recommendations on communication, language and speech in Phelan-McDermid syndrome.

Phelan-McDermid syndrome is a genetic condition primarily caused by a deletion on the 22q13.3 region or a likely pathogenic/pathogenic variant of SHANK3. The main features comprise global developmental delay, marked impairment or absence of speech, and other clinical characteristics to a variable degree, such as hypotonia or psychiatric comorbidities. A set of clinical guidelines for health professionals covering relevant aspects of clinical management have been written by the European PMS Consortium, and consensus has been reached regarding final recommendations. In this work, attention is given to communication, language and speech impairments in PMS, and the findings from available literature are presented. Findings from the literature review reveal marked speech impairment in up to 88% of deletions and 70% of SHANK3 variants. Absence of speech is frequent and affects 50%-80% of the individuals with PMS. Communicative skills in the expressive domain other than spoken language remain understudied, but some studies offer data on non-verbal language or the use of alternative/augmentative communication support. Loss of language and other developmental skills is reported in around 40% of individuals, with variable course. Deletion size and possibly other clinical variables (e.g., conductive hearing problems, neurological issues, intellectual disability, etc.) are related to communicative and linguistic abilities. Recommendations include regular medical check-ups of hearing and the assessment of other factors influencing communication, thorough evaluation of preverbal and verbal communicative skills, early intervention, and support via alternative/augmentative communication systems.

Haemophilia B, severe childhood obesity and other extra-haematological features associated with similar 4Mb-deletions on Xq27: Clinical findings, molecular insights and literature update.

INTRODUCTION: Haemophilia B (HB) is associated with pathogenic variants in F9. Hemizygous deletions encompassing the entire F9 and proximate genes may express extra-haematological clinical phenotypes. AIM: To analyse the genotype/phenotype correlations in two unrelated boys with severe early childhood obesity (SCO), global developmental delay (GDD) and similar bleeding phenotype associated with comparable Xq27 deletions spanning the entire F9 and proximate genes, and characterise the pathogenic events estimating the most likely mutational mechanism involved. METHODS: Entire F9-deletions were detected in three hemizygous unrelated probands with HB: two cases, C#1/C#2, presented SCO and GDD and a control patient (Co), who only had severe bleeding symptoms. Dense SNP-array and case-specific STS walking scan allowed characterisation of the deletion breakpoints. Extensive use of bioinformatics, statistics and clinical databases allowed the investigation of genotype-phenotype associations. RESULTS: Patients C#1/C#2 and Co resulted in a complete F9 and additional gene deletions of variable extensions on Xq26.3-Xq27.2 (C#1/C#2/Co: 4.3Mb/3.9Mb/160Kb). C#1/C#2 common deleted gene SOX3 is directly associated with SCO, GDD and pituitary hypothyroidism (PH) whilst C#2 extra-deleted gene MAGEC2 indirectly relates to anal atresia (AA). Breakpoint analysis revealed the involvement of the mechanisms of Alu/Alu recombination for the first time in HB and non-homologous or alternative end-joining. CONCLUSION: Our results represent the first report of unrelated patients with HB, SCO and GDD. This study and the literature update expand the spectrum of clinical findings and molecular insights observed in patients with HB caused by complete F9 and nearby SOX3 and MAGEC2 gene deletions, which may configure a contiguous gene syndrome.